Haemofiltration system

ABSTRACT

Hemodiafiltration system for treating blood, comprising a membrane module ( 1 ) in whose housing ( 2 ) hollow-fiber membranes ( 3 ) embedded at their ends in first and second sealing compounds ( 4,5 ) joined to the inner wall of the housing in a fluid-tight manner are arranged in the direction of the longitudinal extent, the membrane module ( 1 ) also having a dialyzate space ( 12 ) and a substituate space ( 11 ) separated from the dialyzate space ( 12 ) in a fluid-tight manner by a continuous dividing wall ( 10 ), and further comprising means for delivering ( 18,19 ) and withdrawing a dialyzate to and from the dialyzate space ( 12 ), and means for delivering ( 21 ) a substituate to the substituate space ( 11 ), the same hollow-fiber membranes ( 3 ) being used for blood treatment, filtration of the substituate, and delivery of the substituate to the blood, and an exterior space being formed around the hollow-fiber membranes ( 3 ) that is delimited by the inner wall of the housing ( 2 ) and sealing compounds ( 4,5 ) and divided along the longitudinal extent of the housing ( 2 ) by the dividing wall ( 10 ) into the substituate space ( 11 ) and the dialyzate space ( 12 ), the dividing wall ( 10 ) enclosing each individual hollow-fiber membrane ( 3 ).

DESCRIPTION

[0001] The invention relates to a hemodiafiltration system for treatingblood, comprising a membrane module having a cylinder-shaped housingwith a longitudinal extent, in which housing a bundle of hollow-fibermembranes having semipermeable walls capable of supporting fluid flowthrough their lumina. The ends of the hollow-fiber membranes areembedded in a fluid-tight manner in first and second sealing compoundsjoined to the housing inner wall in a fluid-tight manner and arearranged in the direction of the longitudinal extent. There is adialyzate space into which a dialyzate inlet arrangement and a dialyzateoutlet arrangement open, as well as a substituate space into which asubstituate inlet arrangement opens, a means for delivering a dialyzatewith a defined volume stream into the dialyzate space via the dialyzateinlet arrangement, a means for withdrawing the dialyzate from thedialyzate space via the dialyzate outlet arrangement, and a means fordelivering a substituate with a defined volume stream into thesubstituate space via the substituate inlet arrangement. The membranemodule is implemented as a integrated unit for blood treatment,filtration of the substituate, and mixing of the substituate with theblood. The substituate and dialyzate spaces being separated from eachother in a fluid-tight manner via a continuous dividing wall. Theinvention furthermore relates to a membrane module forhemodiafiltration.

[0002] Hemodiafiltration is a combined membrane-based process for bloodpurification in which hemodialysis and hemofiltration are conductedconcurrently. This process combines the advantages of convectivesubstance transport in hemofiltration with those of diffusion inhemodialysis. In hemofiltration, blood is passed along one side of themembrane of a hemofilter and a portion of the blood liquid is withdrawnthrough the membrane by ultrafiltration. This partial stream is replacedby a sterile and pyrogen-free substitution liquid, or substituate, thatis delivered to the extracorporeal blood stream either upstream from thehemofilter in the form of pre-dilution or downstream from the hemofilterin the form of post-dilution. In addition, in hemodiafiltration theusual hemodialysis is also conducted, wherein dialyzate is passed alongthe other side of the membrane of the hemodialyzer such that substancesusually eliminated with the urine can be removed through the membrane.

[0003] The combination of diffusive substance transport with convectivesubstance transport in hemodiafiltration permits the advantageousremoval of more than only substances from the blood having a lowmolecular weight that are usually eliminated with the urine. Slowlydiffusing medium-sized molecules with molecular weights from about 1 to55 kD profit especially from the convective substance transport, andthat is all the more so as these molecules increase in size and as thefiltrate stream through the membrane increases. At about 60 kD, themembranes are intended to be essentially impermeable, so that thepatient does not pass more than 4 g of protein from the blood into thedialyzate during a 4-hour treatment.

[0004] In the conventional hemodialysis process, only the amount ofliquid the patient has taken in between the dialysis treatments isremoved from the blood via the dialysis membrane as ultrafiltrate. Theamount of liquid removed in this process is about 6 to 8% of the bloodvolume stream. In conducting current hemodialysis processes, so-calledvolume-controlled dialysis machines are generally used. They control thenet amount of liquid removed according to the preset net filtration bybalancing the dialyzate stream fed to the dialyzer with the dialyzatestream withdrawn from the dialyzer.

[0005] In hemodiafiltration, on the other hand, the amount ofultrafiltrate is significantly higher, from about 20 to 30% of the bloodvolume stream, due to the liquid fraction needed to increase theconvective transport through the membrane. In the end, the net amount ofliquid withdrawn from the patient is the same as that in conventionalhemodialysis. The amount of liquid exceeding that needed to increase theconvective transport is, as noted, replaced by a substituate.

[0006] To conduct hemodiafiltration processes, modified dialysismachines are generally used that permit control of the ultrafiltrationrates and balance the ultrafiltration and substituate volume streams.

[0007] Different requirements are usually imposed with respect to thepurity of the dialyzate and substitution liquids. The dialyzate can beprepared online from fresh water and an electrolyte concentrate, wherethe fresh water is normally germ-free and the electrolyte concentrateinherently sterile. The substitution liquid itself can be preparedonline from the dialyzate, but it is not generally required that thedialyzate prepared online is absolutely sterile and free of endotoxins,pyrogens and CIS.

[0008] Endotoxins are cell remnants of dead bacteria. The endotoxinconcentration is usually determined using the so-called LAL test, abiological assay such as that manufactured by BioWhittaker, Inc., forexample. Pyrogens are temperature-elevating substances. When infused inrabbits, for example, they cause an increase in body temperature.Pyrogens can include endotoxins and exotoxins. The latter are producedby living bacteria. In human blood, these substances lead to stimulationof monocytes that themselves produce cytokines and thus trigger acascade of additional cell stimulations. Today, endotoxins, exotoxins,pyrogens, and other substances from the dialyzate that stimulate theblood are grouped under the abbreviation CIS (cytokine inducingsubstances). One of the relevant cytokines produced by stimulation ofstimulated monocytes is interleukin 6 (IL 6). The determination of CISby detection of IL 6 is described in B. L. Jaber et al., Blood Purif.1998, Vol. 16, pp. 210-219, for example.

[0009] For this reason, the dialyzate for preparing the substitutionliquid should be converted to the sterile and ideally CIS-free state,using a filter, for example. Of course, the substitution liquid preparedin this manner can also be used itself as dialyzate. Modem dialysismachines generally include a facility with which the dialyzate isfiltered online such that it has an endotoxin concentration of less than0.5 EU per ml of dialyzate. As a result, patients experience almost nopyrogen reactions, even in the case of so-called high-flux dialysis,which are frequently observed with dialyzate contaminated withendotoxins. However, with an endotoxin concentration of <0.03 EU/ml,which is the detection limit of the conventional LAL tests, CIS mightstill be present in the dialyzate. The requirement for CIS-freedialyzate is therefore more stringent than that for LAL-negativedialyzate.

[0010] In EP-A 692 269, a hemodiafiltration apparatus is described withtwo blood filters connected in series. The blood filters each containmembranes, one side of which is subjected to a flow of blood to bepurified and the other side to dialyzate flow. The dialyzate fed to thehemodiafiltration apparatus was previously passed through a sterilefilter. In the apparatus described in EP-A 692 269, a transfer ofdialyzate as a substitution liquid directly into the blood takes placein one of the two blood filters in the direction of the blood flow, dueto the positive transmembrane pressure set at this point via themembrane of this blood filter. A negative transmembrane pressure isgenerated in the second blood filter, where separation of a portion ofthe blood liquid and removal into the dialyzate of substances normallyeliminated with the urine take place via diafiltration.

[0011] Such hemodiafiltration apparatus with blood filters connected inseries are complex in operation and can generally not be used incommercially available dialysis machines due to the design and thespecial and complex controls associated with it.

[0012] EP-A 451 429 also discloses a hemodiafiltration apparatus havingtwo membrane modules connected in series. In this case, the firstmembrane module is a hemofilter in which a partial stream of liquid iswithdrawn by ultrafiltration from the blood to be purified, wherein thepartial stream primarily contains the medium-molecular substances to beremoved from the blood. The ultrafiltrate is regenerated in a specialfilter and reintroduced to the blood stream before the latter isdirected into the second membrane module. This blood stream is thensubjected to hemodialysis in the second membrane module.

[0013] In addition to the previously cited disadvantages of separateblood filters connected in series, the hemodiafiltration apparatusdescribed in EP-A 451 429 has the drawback that it requires a specialregenerator that must be used to purify the ultrafiltrate.

[0014] In DE-A 196 07 162, a hemodiafiltration system is described withcontrolled delivery of a substituate and a dialyzate into a dialyzer,wherein the dialyzer is designed as a single component for bloodtreatment, substituate filtering, and mixing of the substituate with theblood to be treated. The dialyzer contains two adjacent membrane modulesin its longitudinally extended housing, each with a bundle ofhollow-fiber membranes. The membrane modules are separated from eachother by a dividing wall substantially parallel to the hollow-fibermembranes. The first membrane module is used for hemodiafiltration andthe second membrane module for sterile filtration of the substituate.The dialyzer further comprises a chamber in which purified substituateis reunited with the blood to be treated.

[0015] While the hemodiafiltration system described in DE-A 196 07 162has a simpler and clearer construction compared to the systems withmultiple blood filters connected in series, the manufacture of thetwo-module dialyzers disclosed in DE-A 196 07 162 is difficult,particularly due in part to the handling of two different hollow-fibermembrane bundles. Furthermore, the membrane modules in the dialyzer arenot arranged rotationally symmetrically, so that there is a risk ofnon-uniform flow, in particular through the external space surroundingthe hollow-fiber membranes of the first membrane module, which is usedfor hemodiafiltration.

[0016] It is therefore an object of the present invention to provide ahemodiafiltration system that has a simple construction, allows apredeterminable and reproducible delivery of substituate and dialyzate,and can be used in volume-controlled dialysis machines without majormodifications. It is a further object of the present invention toprovide a membrane module for hemodiafiltration for use in ahemodiafiltration system, wherein the module enables concurrent sterilefiltration of the substituate.

[0017] The object is, on the one hand, achieved by a hemodiafiltrationsystem in accordance with claim 1, wherein the hollow-fiber membranesare combined into a single bundle and the hollow-fiber membranes areused for blood treatment, filtration of the substituate, and delivery ofthe substituate to the blood. An exterior space delimited by the housinginner wall and the first and second sealing compounds is formed aroundthe hollow-fiber membranes, wherein the exterior space along thelongitudinal extent of the housing is separated by a dividing wall intothe substituate space and the dialyzate space. The dividing wallenclosing each individual hollow-fiber membrane.

[0018] In a preferred embodiment of the hemodiafiltration system of theinvention, the housing of the membrane module used according to theinvention is circularly cylindrical about its longitudinal axis orientedin the direction of the longitudinal extent, and the hollow-fibermembranes are arranged in a bundle that is substantially rotationallysymmetrical about the longitudinal axis.

[0019] In the membrane module of the hemodiafiltration system of theinvention, the ends of the hollow-fiber membranes are each embedded in afluid-tight manner in sealing compounds that also seal off the exteriorspace formed around the hollow fibers with respect to a distributionspace, in which the blood to be treated and introduced into thedistribution space via a blood inlet arrangement is distributed to thelumina of the hollow-fiber membranes, and with respect to a collectionspace in which the blood flowing from the lumina is collected andwithdrawn from the module via a blood outlet arrangement. The ends, openon the face, of the hollow-fiber membranes extend through the respectivesealing compound and are in communication with the distribution andcollection spaces via the lumina, so that the blood to be treated canpass through the membranes.

[0020] Due to the fact that in the membrane module used in thehemodiafiltration system of the invention, the same hollow-fibermembranes are used for blood treatment, filtering of the substituate,and delivery of the substituate to the blood, and that the dialyzate andsubstituate spaces are separated from each other by a dividing wall, thedialyzate and substituate spaces are arranged adjacent to each other atdifferent positions along the hollow-fiber membranes when viewed in thedirection of the extent of the hollow-fiber membranes, with the dividingwall filling out the inner cross-section of the housing. Preferably, thedividing wall in the membrane module used in the hemodiafiltrationsystem of the invention is arranged substantially transversely to thehollow-fiber membranes.

[0021] During use of the hemodiafiltration system according to theinvention, the blood to be purified, which is withdrawn from thepatient, is directed into the membrane module via the blood inletarrangement and through the lumina of the hollow-fiber membranes. By ameans for delivery of dialyzate, which comprises suitable deliverymeans, e.g., in the form of a pump or metering unit for deliveringdialyzate with a defined volume stream, and a dialyzate supply lineconnected to the dialyzate inlet arrangement, fresh dialyzate with adefined volume stream is supplied to the membrane module and introducedinto the dialyzate space via the dialyzate inlet arrangement. In thedialyzate space, the dialyzate is passed along the hollow-fibermembranes, thereby also taking up the ultrafiltrate withdrawn from theblood through the walls of the hollow-fiber membranes viaultrafiltration. Hemodiafiltration of the blood takes place in thedialyzate space area, wherein substances normally eliminated with theurine are removed from the blood via diffusive and convective transportmechanisms. The dialyzate, mixed with the ultrafiltrate, is withdrawnfrom the dialyzate space via the dialyzate outlet arrangement using adialyzate flow pump and conducted away via a dialyzate withdrawal line.

[0022] The substituate is introduced, via dedicated means for deliveryof substituate with a defined volume stream, under increased pressureinto the substituate space via the substituate inlet arrangement anddelivered at that point with a defined volume stream to the bloodflowing through the lumina of the hollow-fiber membranes, via the wallsof the segments of the hollow-fiber membranes located in the substituatespace. The amount of substituate to be delivered per unit of time, i.e.,the substituate volume stream, is the difference between the liquidstream withdrawn from the blood in the dialyzate space area viaultrafiltration and the net filtration controlled and fixedly preset bythe dialysis machine. In this process, the substituate volume stream isgenerally smaller than the dialyzate stream introduced into thedialyzate space. Depending on the direction of blood flow through thehollow-fiber membranes, the substituate can be delivered to the bloodbefore the blood is subjected to hemodiafiltration (pre-dilution) orafter it has been subjected to hemodiafiltration (post-dilution).Control of the dialyzate circuit, including substituate delivery, isperformed by a balancing unit connected to the dialyzate circuit. Thenet filtration, i.e., the net amount of liquid to be withdrawn from theblood in the dialyzate space area, is adjusted by an ultrafiltrate pumpcoupled to the balancing unit using closed-loop control techniques.

[0023] In an embodiment of the hemodiafiltration system of theinvention, the substituate delivery means is physically and completelyseparate from the dialyzate delivery means and comprises suitabledelivery means for delivering the substituate with a defined volumestream, for example, in the form of a pump or a metering unit, and,separate from the dialyzate supply line, a substituate supply line influid communication with the substituate inlet arrangement. In thiscase, the dialyzate delivery means and substituate delivery means mustbe controlled separately by closed-loop control systems coupled to oneanother.

[0024] In a preferred embodiment of the hemodiafiltration system of theinvention, the substituate delivery means and dialyzate delivery meansare coupled to one another. It is especially preferred for the couplingto be implemented such that the substituate delivery means and thedialyzate delivery means comprise a common multiple pump to which adialyzate supply line in communication with the dialyzate inletarrangement and a substituate supply line in communication with thesubstituate inlet arrangement are connected. This multiple pumpcomprises a common pump drive to which two separate pump heads arecoupled. The ratio of the substituate volume stream to that of thedialyzate can be adjusted via the delivery rate of the pump heads.

[0025] In another especially preferred embodiment, the dialyzatedelivery means comprises a dialyzate delivery device and dialyzatesupply line, and the substituate delivery means comprises a substituatesupply line, and the substituate supply line branches off from thedialyzate supply line via a diversion. In this case, the substituate iswithdrawn from the dialyzate supply line by the diversion as a partialstream from the dialyzate flowing through the dialyzate supply line anddirected via the substituate supply line and substituate inletarrangement into the substituate space, from which it is delivered tothe blood flowing through the hollow-fiber membranes via their walls.

[0026] To establish a defined substituate stream, it is especiallypreferable for a pump to be inserted in the substituate supply line,wherein the pump provides a defined delivery of the substituate, i.e.,allows adjustment of the substituate volume stream. It is preferred inthis case for the pump to be controllable. The adjustment of thedialyzate and substituate volume streams, and the ratio of these volumestreams to each other, can also be performed by throttles. For thisreason, in a likewise especially preferred embodiment, a throttle isinserted in the dialyzate supply line in the area between the diversionand dialyzate inlet arrangement or into the substituate and dialyzatesupply lines in the area between the diversion and dialyzate inletarrangement, the throttle providing a means for adjusting the ratio ofsubstituate volume stream to dialyzate volume stream.

[0027] A throttle in this case is understood to be a defined restrictionof a flow cross-section to selectively generate a defined pressure dropwhen a fluid flows through this restriction. That is, the throttleexhibits a reduced flow cross-section compared to the flow cross-sectionbefore and after the throttle with respect to the direction of flow. Inthis embodiment, the flow cross-section of the throttle has a definedfixed value independent of the passing medium, or it can be adjusted toa defined value independent of the passing medium. In such throttles,the pressure drop arising during flow can be predetermined. Throttleswith a fixed flow cross-section are, for example, perforated or slitdiaphragms having a flow cross-section preferably adjustable to thefixed cross-section, or capillary tubes with defined diameters.Throttles with adjustable cross-section are, for example, valves orthrottle flaps inserted into piping. It is preferred for the throttlesof the invention to be adjustable, and it is especially preferred forthe throttles to be controllable.

[0028] The dialyzate stream is introduced into the dialyzate space bythe throttles arranged in the dialyzate and/or substituate supply linesand the substituate stream, and thereby the ratio of the two streams toone another can be adjusted to a defined value in a simple manner.

[0029] The hemodiafiltration system of the invention is considerablysimpler compared to prior art systems due to the membrane moduleemployed according to the invention, in which, during use, the dilutionof the blood with substituate, as required for hemodiafiltration, andthe hemodiafiltration are integrated in a single membrane module in asimple, controllable, and reproducible manner, and which, likeconventional hemodialyzers, contains a single bundle of hollow-fibermembranes. At the same time, the concept of the invention of separatelydelivering dialyzate and substituate via respective means into thedialyzate and substituate spaces, which are separated from each other ina fluid-tight manner, permits selective adjustment of the requireddialyzate and substituate volume streams to adapt to thehemodiafiltration application. Furthermore, using the hemodiafiltrationsystem of the invention, hemodiafiltration can be conducted incommercially available dialysis machines with volume-stream controlledultrafiltration.

[0030] DE-A 28 51 929 discloses a module design on the basis ofhollow-fiber membranes, herein the dialyzate space is divided into twosections by an impermeable dividing wall. In one embodiment, dialyzateis directed through the one section, which is provided with an inletarrangement and an outlet arrangement in order to remove, by diffusion,substances normally eliminated with the urine from the blood flowingthrough the hollow-fiber membranes. The second section, which isprovided with an outlet arrangement, is subjected to a partial vacuum inorder to extract, via the walls of the hollow-fiber membranes, afiltrate from the blood flowing through the membranes. DE-A 28 51 929,however, does not disclose the inclusion of such a membrane module in ahemodiafiltration system or the use of such a membrane module in ahemodiafiltration process.

[0031] Therefore, a further subject of the invention is the use of amembrane module having a cylinder-shaped housing with a longitudinalextent, in which housing a bundle of hollow-fiber membranes havingsemipermeable walls, capable of supporting fluid flow through theirlumina, and embedded at their ends in first and second sealing compoundsjoined to the housing inner wall in a fluid-tight manner is arranged inthe direction of the longitudinal extent, and in which housing anexterior space delimited by the housing inner wall and the first andsecond sealing compounds is formed around the hollow-fiber membranes.The exterior space along the longitudinal extent of the housing isdivided by a continuous dividing wall into a dialyzate space and asubstituate space separated from the dialyzate space in a fluid-tightmanner. The dividing wall encloses each individual hollow-fibermembrane, to conduct a hemodiafiltration process in which the bundle ofhollow-fiber membranes is used, in addition to the actual bloodtreatment, to filter the substituate and deliver the substituate to theblood.

[0032] In the membrane module of the hemodiafiltration system accordingto the invention, the delivery of the substituate to the blood can takeplace before or after the blood is subjected to hemodiafiltration in thedialyzate space area. In an individual case, it is also possible todivide the substituate space, and thus the delivery of the substituateto the blood, along the extent of the hollow-fiber membranes and deliverone part of the substituate to the blood before and one part after thehemodiafiltration. In this case, in the membrane module of theinvention, for example, two substituate-space sections are arrangedalong the extent of the hollow-fiber membranes adjacent to the embeddingpoint of the hollow-fiber membrane ends, each section is separated by adividing wall from an intermediate dialyzate space in a fluid-tightmanner. Correspondingly, it is also possible to divide the dialyzatespace, and thereby the hemodiafiltration, and to arrange twodialyzate-space sections in the membrane module, for example, along theextent of the hollow-fiber membranes adjacent to the embedding points ofthe hollow-fiber membrane ends. Each section is separated by a dividingwall from an intermediate substituate space.

[0033] For applications in which a post-dilution of the blood withsubstituate takes place, the blood flows into the hollow-fiber membranesat the end of the membrane module facing the dialyzate space and throughthe membranes toward the end facing the substituate space. The requiredliquid is first withdrawn from the blood in the dialyzate space area byultrafiltration and then substituate delivered to the blood in thesubstituate space area. In this process, it is advantageous if thedialyzate inlet arrangement is adjacent to the dividing wall and thedialyzate outlet arrangement adjacent to the sealing compound delimitingthe dialyzate space and enclosing the ends of the hollow-fibermembranes. The dialyzate then flows through the dialyzate space in adirection opposite that of the blood flow.

[0034] For applications in which a pre-dilution of the blood withsubstituate takes place, the blood flows into the hollow-fiber membranesat the end of the membrane module facing the substituate space andthrough the membranes toward the end facing the dialyzate space. In thisprocess, substituate is first delivered to the blood in the substituatespace area and then the required liquid withdrawn by ultrafiltration inthe dialyzate space area. In this case, it is advantageous if thedialyzate inlet arrangement is adjacent to the sealing compounddelimiting the dialyzate space and enclosing the ends of thehollow-fiber membranes, and the dialyzate outlet arrangement is adjacentto the dividing wall so that the dialyzate flows through the dialyzatespace in a direction opposite that of the blood flow.

[0035] In conducting hemodiafiltration, an external sterile filter isoften connected upstream from the actual membrane module, providingsterile filtration of the dialyzate or at least the liquid delivered asa substituate. Generally, however, a sterile filtration of the entiredialyzate is unnecessary, since in the end the portion of the dialyzatepassed as dialyzate along the hollow-fiber membranes is not subject tothe stringent purity requirements applying to the substituate. For thesterile filtration of the substituate, in an advantageous embodiment ofthe hemodiafiltration system according to the invention, a sterilefilter is arranged within the membrane module around the hollow-fiberbundle in the substituate space area, the filter enclosing thehollow-fiber membrane bundle.

[0036] The invention further relates to a membrane module comprising acylinder-shaped housing with a longitudinal extent, in which housing abundle of hollow-fiber membranes with semipermeable walls and capable ofsupporting fluid flow through their lumina is arranged in the directionof the longitudinal extent of the housing, the ends of the hollow-fibermembranes being embedded in a fluid-tight manner in first and secondsealing compounds joined to the housing inner wall in a fluid-tightmanner such that an exterior space delimited by the first and secondsealing compounds and the housing inner wall is formed around thehollow-fiber membranes. The exterior space along the longitudinal extentof the housing is divided into a dialyzate space and a substituate spaceby a dividing wall that encloses each hollow-fiber membrane and isarranged substantially transversely to the hollow-fiber membranes. Thedialyzate space has an inlet arrangement and an outlet arrangement forintroducing and withdrawing a dialyzate and the substituate space has atleast one opening for introducing a substituate, wherein a sterilefilter is arranged in the substituate space area between the substituateinlet arrangement and the hollow-fiber membranes located in thesubstituate space. The sterile filter divides the substituate space intoan outer substituate-space section and an inner substituate-spacesection that is spatially separated from the outer substituate-spacesection by the sterile filter. The outer substituate-space section is influid communication with the substituate inlet arrangement and thehollow-fiber membranes is arranged in the inner substituate-spacesection.

[0037] Spatial separation in this case is understood to be the state inwhich a fluid introduced into the outer substituate-space section by thesubstituate inlet arrangement can enter the inner substituate-spacesection only by the sterile filter itself, i.e., the sterile filter actsas a so-called dead-end filter.

[0038] In a preferred embodiment of the membrane module of theinvention, the sterile filter is arranged around and encloses thehollow-fiber membrane bundle. In this preferred embodiment, the sterilefilter divides the substituate space perpendicularly to the hollow-fibermembranes into the outer substituate-space section, wherein a uniformdistribution of the substituate to the sterile filter can take place,and the inner substituate-space section contains the bundle ofhollow-fiber membranes. A possibly pleated flat membrane can be usedadvantageously as a sterile filter. It is advantageous to use a flatmembrane that is consistently microporous. The sterile filter ispreferably impermeable to endotoxins and especially preferablyimpermeable to CIS, thereby ensuring during use the delivery of asterile substituate to the hollow-fiber membranes that is free ofendotoxins and pyrogens and preferably of CIS. In this case, a sterilefilter impermeable to endotoxins is understood to be one for which, infiltering a contaminated dialyzate with an endotoxin concentration of upto 30 EU/ml at a filtration rate of 150 ml/min over 4 hours through thesterile filter, the filtrate has an endotoxin concentration below thedetection limit of conventional tests, i.e., below about 0.03 EU/ml. Theendotoxin concentration in this case is determined using conventionalLAL tests such as those sold and described by BioWhittaker, Inc.(MULTI-TEST LIMULUS AMEBOCYTE LYSATE PYROGENT®).

[0039] In individual cases, when employing the membrane module of theinvention or used in the hemodiafiltration system according to theinvention, it is also possible to embed additional semipermeablemembrane elements in the sealing compound adjacent to the substituatespace in which the hollow-fiber membrane ends are embedded in order toincrease the substituate stream to be delivered to the blood. The flowthrough these membrane elements is then performed in dead-end mode, andthey provide fluid communication between the substituate space and thespace on the other side of the sealing compound, wherein this space isthe distribution or collection space for the blood depending on theembodiment of the membrane module of the invention. A portion of thesubstituate can likewise be delivered via these membrane elements to theblood then located in the adjacent collection or distribution space.These semipermeable membrane elements can be present, for example, inthe form of capillary membranes that are closed at one end, arepreferably consistently microporous, are embedded in the sealingcompound, and extend into the substituate space at their closed end.These membrane elements are, like the aforementioned sterile filter,preferably impermeable to endotoxins and especially preferably to CIS.Concerning the definition of endotoxin and CIS impermeability and therespective measurement methods, refer to the preceding discussion.

[0040] For use, it is advantageous for the dividing wall of the membranemodule of the invention or used in the hemodiafiltration systemaccording to the invention to be made of a substantially dimensionallystable material, i.e., a material that in use substantially retains itsdimensions under the then prevailing conditions and in particular doesnot swell in the presence of the liquids used in this case, i.e.,primarily the dialyzate. To simplify manufacture, the dividing wall ispreferably composed of a cured sealing compound in which thehollow-fiber membranes are embedded such that the dividing wall encloseseach hollow-fiber membrane. It is especially preferable for the dividingwall and first and second sealing compounds to be made of the samematerial. In this case, the materials commonly used as sealing compoundsfor embedding hollow-fiber membranes, such as cured polyurethane resins,epoxy resins, and the like can be used.

[0041] In the use of the hemodiafiltration system or membrane module ofthe invention, a maximally uniform distribution of substituate anddialyzate over the bundle cross-section is necessary in the membranemodule. A uniform distribution can be achieved by an appropriate housingdesign. Preferably, the housing of the membrane module is designed suchthat it tightly encloses, with its inside, the bundle of hollow-fibermembranes in the predominant portion of the dialyzate space and exhibitsan expansion of its cross-section in the area of the sealing compounds,dividing wall, and substituate space. In an advantageous embodiment,ring-shaped spaces are thereby formed around the bundle of hollow-fibermembranes in these areas in order to distribute the dialyzate over thehollow-fiber membrane bundle, collect the dialyzate from the membranebundle, and/or distribute the substituate over the bundle.

[0042] Preferably, the bundle has, at least in the predominant portionof the dialyzate space, a packing density of the hollow-fiber membranesbetween 40 and 65%, in reference to the bundle cross-sectional area andsubstantially uniform in this area over the extent of the bundle. It hasbeen observed that, for the membrane module of the invention or usedaccording to the invention, such packing densities allow good removalfrom the blood of the substances normally eliminated with the urine.

[0043] In a likewise advantageous embodiment, the housing of themembrane module is designed such that it tightly encloses, with itsinside, the bundle of hollow-fiber membranes in the dialyzate space areaand exhibits an expansion of the housing cross-section in the area ofthe sealing compounds, dividing wall, and substituate space, and thehollow-fiber membrane bundle is arranged in the housing such that thecross-section of the hollow-fiber membrane bundle expands in the area ofthe dividing wall and substituate space. The packing density of thehollow-fiber membranes in this area is thereby less than in thepredominant portion of the dialyzate space. It is especially preferredfor the packing density of the hollow-fiber membrane bundle to besubstantially homogeneous over the cross-section in the area of theexpanded cross-section. As a result, the hollow-fiber membranes in theinterior of the bundle are also easily accessible to the dialyzate orsubstituate, and the substituate flows uniformly into all hollow-fibermembranes of the bundle. The manufacture of the membrane module is alsosimplified through this embodiment since in the case of a dividing wallhaving a sealing compound, the sealing compound can better enclose theindividual hollow-fiber membranes when they are embedded. In itsexpanded portion, the bundle preferably has a packing density between 20and 55%, in reference to the respective bundle cross-sectional area.

[0044] To conduct an efficient hemodiafiltration, it is necessary that asufficiently large exchange surface area be available for diafiltrationin order to efficiently remove the substances normally eliminated withthe urine from the blood. On the other hand, a sufficient membranesurface area must also be available in order to permit reliable deliveryof the required amount of substituate to the blood. It is found for themembrane module of the present invention that, when viewed in thedirection of the extent of the hollow-fiber membranes, the ratioL_(d)/L_(s) of the length L_(d) of the dialyzate space to the lengthL_(s) of the substituate space should preferably be greater than 3. Forthis reason, the ratio L_(d)/L_(s) is preferably between 3 and 20 andespecially preferably between 5 and 15.

[0045] To likewise provide as large a membrane surface area as possiblefor substituate delivery to the blood and for hemodiafiltration, thedividing wall of the membrane module should be as thin as possible. Onthe other hand, a certain minimum thickness is necessary to ensuresufficient stability of the dividing wall. It is therefore advantageousfor the dividing wall to have a thickness between 1 and 15 mm andespecially advantageous to have a thickness between 5 and 10 mm.

[0046] For efficient hemodiafiltration, it is necessary to generate asufficiently high convective transport in order to remove in particularthe slowly-diffusing substances normally eliminated with the urine,having medium molecular weight. Moreover, it is advantageous if only arelatively small section of the hollow-fiber membrane bundle is neededfor the delivery of substituate to the blood. This means that asufficiently high filtrate flow through the membrane wall must berealizable. For this reason, the hollow-fiber membranes present in themembrane module of the invention or used according to the invention havean ultrafiltration rate for water between 20 and 1500 mL/(h·m²·mmHg).The ultrafiltration rate in this case is determined using the methoddescribed in DE-A 195 18 624, and express reference is hereby made toits disclosure in this regard.

[0047] For the reliable operation of the hemodiafiltration system of theinvention, it is important that no undesired contamination of the bloodflowing through the hollow-fiber membranes with bacteria, endotoxins, orpyrogens occurs, in particular when delivering the substituate to theblood. As previously discussed, the dialyzate and/or at least thesubstituate can, to this end, be subjected to a sterile filtration in aseparate sterile filter or one integrated in the membrane module of thehemodiafiltration system according to the invention. Alternatively or inaddition, this sterile filtration can also take place in thehollow-fiber membranes themselves of the membrane module of thehemodiafiltration system of the invention. Therefore, in a preferredembodiment the hollow-fiber membranes are impermeable to endotoxins andespecially preferably impermeable to cytokine-inducing substances. Theimpermeability in this case can be achieved by an appropriately adjustedpore size of the functional separation layer of the membranes and/or byadsorptive properties of the hollow-fiber membranes. Concerning thedefinition of endotoxin and CIS impermeability and the respectivemeasurement methods, refer to the preceding discussion.

[0048] The hollow-fiber membranes used according to the inventionpreferably have an inside diameter between 140 and 260 pm, with a wallthickness preferably between 5 and 100 μm and more preferably between 20and 60 μm. Membrane materials are preferably those having good bloodcompatibility. This includes polymers from the group of cellulosicpolymers such as cellulose or regenerated cellulose, modified cellulosesuch as cellulose esters, cellulose ethers, amine-modified celluloses,and mixtures of cellulosic polymers, from the group of syntheticpolymers such as polyacrylonitrile and corresponding copolymers,polyarylsulfones, and polyarylethersulfones such as polysulfone orpolyethersulfone, polyamides, polyether block amides, polycarbonates, orpolyesters, as well as modifications, blends, mixtures, or copolymersderived from these polymers. These polymers or polymer mixtures cancontain additional polymers such as polyethylene oxide,polyhydroxyether, polyethylene glycol, polyvinylpyrrolidone, polyvinylalcohol, or polycaprolactone as additives. In individual cases, themembrane can, for example, also have been subjected to a surfacemodification in order to give certain properties to the membranesurface, for example, in the form of certain functional groups, or toachieve the hydrophilation of an otherwise hydrophobic membrane on itssurfaces, as is described for example in JP-A 101 18472.

[0049] No restrictions are placed on the construction of the bundle ofhollow-fiber membranes arranged in the membrane module of thehemodiafiltration system of the invention, i.e., the arrangement of thehollow-fiber membranes in the bundle. A good flow around the individualhollow-fiber membranes should be ensured, however. In an advantageousconstruction, the hollow-fiber membranes are substantially parallel toeach other and to the longitudinal axis of the bundle and the spacingbetween them is maintained by textile threads. This can be achieved, forexample, before the bundle is assembled, by using the textile threads toweave the hollow-fiber membranes to form a mat or ribbon of parallelhollow-fiber membranes and then configuring them to form a bundle. Thebundle of hollow-fiber membranes contained in the membrane module of theinvention can also be composed of bundle sections, as long as during useeach of the hollow-fiber membranes of the bundle contributes to bloodtreatment, filtration of the substituate, and delivery of thesubstituate to the blood. Such a construction of bundle sections, inwhich the sections are wrapped with threads to improve the flow aroundthe hollow-fiber membranes and the hollow-fiber membranes within thesections are spaced using support threads, is described in EP-A 732 141,for example. Moreover, the hollow-fiber membranes can also exhibit anundulation.

[0050] The invention will now be explained in more detail with referenceto the figures, which are simplified schematic representations:

[0051]FIG. 1 shows a segment of a hemodiafiltration system of theinvention, with a membrane module employed therein, in longitudinalsection illustrating a process with post-dilution of the blood.

[0052]FIG. 2 shows a segment of a hemodiafiltration system of theinvention, with a membrane module employed therein, in longitudinalsection illustrating a process with pre-dilution of the blood.

[0053]FIG. 3 shows a segment of a longitudinal section through amembrane module of the invention, or used in the hemodiafiltrationsystem according to the invention, with a sterile filter integrated intothe module housing.

[0054]FIG. 4 is a schematic representation of a hemodiafiltration systemof the invention, illustrating a process with post-dilution of blood.

[0055]FIG. 5 is a schematic representation of a hemodiafiltration systemof the invention, illustrating a process with pre-dilution of blood.

[0056]FIG. 1 is a schematic representation of a segment of ahemodiafiltration system according to the invention with membrane module1 in longitudinal section. The membrane module 1 has a cylinder-shapedhousing 2 in which a bundle of hollow-fiber membranes 3 is arranged,wherein the membranes are oriented in the direction of the longitudinalextent of the housing. The ends of the hollow-fiber membranes areembedded in a fluid-tight manner in sealing compounds 4, 5, which arethemselves joined to the inner wall of housing 2 in a fluid-tightmanner. The hollow-fiber membranes are embedded in sealing compounds 4,5 such that their ends extend through the sealing compounds 4, 5 andtheir lumina open into a distribution space 6 and a collection space 7.The distribution space 6 has a blood inlet arrangement 8 and thecollection space 7 has a blood outlet arrangement 9.

[0057] Encircling the hollow-fiber membranes 3 between sealing compounds4, 5 and the inner wall of housing 2 is an exterior space that isdivided into a substituate space 11 and a dialyzate space 12 along theextent of the hollow-fiber membranes 3 by a dividing wall 10 runningtransversely to the hollow-fiber membranes 3 and made for example of acured epoxy or polyurethane sealing compound. The dividing wall 10encloses the individual hollow-fiber membranes 3 and is joined in afluid-tight manner to the housing inner wall, so that the substituatespace 11 and dialyzate space 12 are separated from each other in afluid-tight manner.

[0058] The dialyzate space has a dialyzate inlet arrangement 13 anddialyzate outlet arrangement 14, and the substituate space has asubstituate inlet arrangement 15. To ensure a good distribution ofdialyzate and substituate in the dialyzate space 12 and substituatespace 11, respectively, during use, housing 2 in the membrane moduleillustrated in FIG. 1 has an expanded cross-section in the area ofdividing wall 10 and substituate space 11. In the area of outletarrangement 14, the cross-section of housing 2 is also expanded in orderto allow uniform withdrawal of the dialyzate from the module.

[0059]FIG. 1 schematically indicates a process for hemodiafiltration inwhich a post-dilution of the blood with substituate takes place, i.e.,the ultrafiltrate is first removed from the blood as it flows throughthe membrane module and the substituate is then delivered to the blood.During use, the blood, indicated by arrows 16, flows via the blood inletarrangement 8 into the distribution space 6, through the lumina of thehollow-fiber membranes 3, then out of the hollow-fiber membranes 3 intothe collection space 7, and is conducted out of the membrane module,i.e., out of the hemodiafilter, via the blood outlet arrangement 9.

[0060] The dialyzate, indicated by arrows 17, is introduced into thedialyzate space 12 via dialyzate supply line 19 connected to inletarrangement 13 using a pump 18, which serves as a delivery device, andflows through the dialyzate space 12 in a direction opposite to that ofthe blood flow. In this process, the dialyzate 17 takes up theultrafiltrate flowing out through the walls of the hollow-fibermembranes 3, together with the substances removed from the blood thatare normally eliminated with the urine. The dialyzate 17, mixed with theultrafiltrate, is withdrawn from the dialyzate space 12 via the outletarrangement 14.

[0061] In the embodiment illustrated in FIG. 1, the substituaterepresented by arrow 20 is withdrawn from the dialyzate flowing throughdialyzate supply line 19 as a partial stream via a substituate supplyline 21 branching off from the dialyzate supply line 19 and introducedinto the substituate space 11 via the inlet arrangement 15, where itflows through the hollow-fiber membranes extending through at thislocation and mixes with the blood flowing through the hollow-fibermembranes 3. To establish a defined ratio of dialyzate volume stream tosubstituate volume stream, a throttle 22 is inserted in the dialyzatesupply line 19 in the area between the diversion and the dialyzate inletarrangement 13.

[0062] The membrane module represented schematically in longitudinalsection in FIG. 2 corresponds to a substantial extent to that in FIG. 1,so that the same components are designated with the same referencenumbers and a detailed description is not repeated. FIG. 2, however,shows a segment of a hemodiafiltration system in which, during use, apre-dilution of the blood takes place during hemodiafiltration, i.e.,substituate is initially delivered to the blood as it flows through themembrane module and the ultrafiltrate is then withdrawn.

[0063] During hemodiafiltration, the blood 16 is directed via bloodinlet arrangement 8 and distribution space 6 into, and flows through,the hollow-fiber membranes 3. In this process, substituate is deliveredto the blood in the area of substituate space 11 and the blood therebydiluted with substituate before it passes, on its way through thehollow-fiber membranes 3, through the area of dialyzate space 12, inwhich the required liquid is withdrawn from the blood by ultrafiltrationthrough the walls of the hollow-fiber membranes and the substancesnormally eliminated with the urine are removed thereby. The purifiedblood, adjusted to the required liquid content, leaves the membranemodule of the invention via the blood outlet arrangement 9.

[0064] The dialyzate 17 is introduced via the inlet arrangement 13,which in this case is at the end of the dialyzate space facing away fromthe dividing wall 10, into the dialyzate space and flows through thedialyzate space in a direction opposite to that of the blood flow in thedirection of dividing wall 10. In this process, it takes up theultrafiltrate with the substances removed from the blood that arenormally eliminated with the urine and is then withdrawn from thedialyzate space 12 via the outlet arrangement 14 located in the vicinityof the dividing wall 10. As also shown in FIG. 1, the substituate iswithdrawn as a partial stream from the dialyzate flowing through thedialyzate supply line 19 via a substituate supply line 21 branching offfrom the dialyzate supply line 19, introduced into the substituate space11 via the inlet arrangement 15, and from there delivered to the bloodvia the hollow-fiber membranes 3. In the embodiment depicted in FIG. 2,however, a pressure-boosting pump 23 is inserted in the substituatesupply line 21 to adjust the ratio of the dialyzate volume stream to thesubstituate volume stream.

[0065]FIG. 3 shows, in an enlarged representation compared to that ofFIGS. 1 and 2, a segment of a membrane module 1 of the invention, orused in a hemodiafiltration system according to the invention,comprising the substituate space and the dividing wall 10. The membranemodule segment depicted in FIG. 3 also corresponds substantially to thatin FIG. 1, so that the same components are designated with the samereference numbers and a detailed description is not repeated.

[0066] The membrane module embodiment depicted in FIG. 3 has a sterilefilter 24 integrated into housing 2 for sterile filtration of thesubstituate 20. The sterile filter 24, preferably in the form of a flatmembrane impermeable to bacteria and endotoxins, encloses thehollow-fiber membrane bundle in the substituate space area and dividesthe substituate space into an outer substituate-space section 25 and aninner substituate-space section 26, each of which is separated in afluid-tight manner from dialyzate space 12 via dividing wall 10. Thesterile filter and hollow-fiber membranes 3 can readily be embedded inthe sealing compound 5 and dividing wall 10. During use of theembodiment of the membrane module according to the invention, as shownin FIG. 3, the substituate 20 introduced into the housing via the inletarrangement 15 is distributed uniformly in the outer substituate-spacesection 25 over the entire periphery and flows completely through thesterile filer 24, where it is subjected to sterile filtration. Afterflowing through the sterile filter 24, the substituate 20 is distributedover the inner substituate-space section 26 and flows from there throughthe walls of the hollow-fiber membranes 3 into the blood flowing throughthem.

[0067]FIG. 4 is a schematic representation of the basic construction ofa hemodiafiltration system of the invention, comprising a membranemodule 1 with a dividing wall 10, as is shown in FIG. 1. Thehemodiafiltration system of FIG. 4 is suitable for hemodiafiltrationprocesses in which a post-dilution of the blood with substituate isperformed. The blood taken from the patient is delivered to membranemodule 1 in the direction of arrow “a” via a blood supply line 27 andthe blood inlet arrangement 8 of the membrane module 1 serving as ahemodiafilter and passed through the lumina of the hollow-fibermembranes arranged in the membrane module. The purified blood iswithdrawn from membrane module 1 via the blood outlet arrangement 9 andre-introduced to the patient in the direction of arrow “a” via bloodwithdrawal line 28 and drip chamber 29.

[0068] Dialyzate is delivered in the direction of arrow “b” via thedialyzate supply line 19 and dialyzate inlet arrangement 13 into thedialyzate space of the hemodiafilter 1, flowing through the dialyzatespace toward the dialyzate outlet arrangement 14 in a direction oppositeto that of the blood flow, thereby taking up the ultrafiltrate,containing the substances normally eliminated with the urine, that iswithdrawn from the blood via the hollow-fiber membranes. The dialyzate,enriched with the ultrafiltrate, leaves the membrane module via theoutlet arrangement 14 and is conducted away via the dialyzate withdrawalline 30 in the direction of arrow “c” using dialyzate flow pump 31 andultrafiltrate pump 33.

[0069] In the embodiment of the hemodiafiltration system of theinvention as depicted in FIG. 4, the substituate to be delivered to theblood is introduced through the substituate supply line 21 branching offfrom the dialyzate supply line 19 and via the substituate inletarrangement 15 into the substituate space of membrane module 1, fromwhich it is delivered to the blood flowing in the hollow-fiber membranesvia their walls. In the present case, a pump 23 is located in thesubstituate supply line 21, which is preferably controllable and viawhich the substituate volume stream, and thus the ratio of dialyzatevolume stream to substituate volume stream, can be adjusted.

[0070] The balancing unit 32 provides for controlling the circulation ofthe dialyzate, and the ultrafiltrate pump 33 for adjusting the netfiltrate stream withdrawn from the blood in the area of the dialyzatespace. In this process, the balancing unit 32 functions such that thevolume stream delivered via pump 31 is replaced by an identically largevolume stream of fresh dialyzate.

[0071]FIG. 5 schematically depicts another embodiment of thehemodiafiltration system of the invention. The major components of thehemodiafiltration system of FIG. 5 correspond to those of FIG. 4, sothat the same components are designated with the same reference numbers.In contrast to the hemodiafiltration system of FIG. 4, however, thehemodiafiltration system of FIG. 5 is suited to hemodiafiltrationprocesses in which a pre-dilution of the blood with substituate isperformed. The dialyzate, which is delivered via the dialyzate supplyline 19 to membrane module 1 serving as a hemodiafilter, flows via thedialyzate inlet arrangement 13 into the dialyzate space of thehemodiafilter, the dialyzate inlet arrangement 13 being located in thepresent case at the end of the hemodiafilter facing toward the bloodoutlet arrangement 9. In the dialyzate space, the dialyzate flows, in adirection opposite that of the blood, toward the dialyzate outletarrangement 14, which is arranged adjacent to the dividing wall 10,which is merely suggested in this case. The dialyzate, mixed with theultrafiltrate taken up in the dialyzate space, leaves the dialyzatespace via the dialyzate outlet arrangement 14 and is withdrawn via thedialyzate withdrawal line 30 in the direction of arrow “c” usingdialyzate flow pump 31 and ultrafiltrate pump 33.

[0072] In the embodiment of the hemodiafiltration system of theinvention as shown in FIG. 5, the substituate to be delivered to theblood is likewise diverted from the dialyzate stream through asubstituate supply line 21 branching off from the dialyzate supply line19 and introduced via the substituate inlet arrangement 15 into thesubstituate space of membrane module 1, from which it is delivered tothe blood flowing in the hollow-fiber membranes via their walls. In theembodiment of the hemodiafiltration system of the invention as shown inFIG. 5, a throttle 22 is present in the dialyzate supply line 19 betweenthe diversion of the substituate supply line 21 and the dialyzate inletarrangement 13, the throttle being preferably in the form of anadjustable valve by which the ratio of dialyzate volume stream tosubstituate volume stream is adjusted.

What is claimed is:
 1. Hemodiafiltration system for treating blood,comprising a membrane module (1) having a cylinder-shaped housing (2)with a longitudinal extent, in which housing (2) hollow-fiber membranes(3) having semipermeable walls, capable of supporting fluid flow throughtheir lumina, and embedded at their ends in first and second sealingcompounds (4,5) joined to the inner wall of the housing (2) in afluid-tight manner are arranged in the direction of the longitudinalextent, and having a dialyzate space (12) into which a dialyzate inletarrangement (13) and dialyzate outlet arrangement (14) open, as well asa substituate space (11) into which a substituate inlet arrangement (15)opens, and further comprising means for delivering a dialyzate with adefined volume stream into the dialyzate space (12) via the dialyzateinlet arrangement (13), means for withdrawing the dialyzate from thedialyzate space (12) via the dialyzate outlet arrangement (14), meansfor delivering a substituate with a defined volume stream into thesubstituate space (11) via the substituate inlet arrangement (15), themembrane module (1) being implemented as a integrated unit for bloodtreatment, filtration of the substituate, and mixing of the substituatewith the blood, and the substituate space (11) and dialyzate space (12)being separated from each other in a fluid-tight manner via a continuousdividing wall (10), characterized in that the hollow-fiber membranes (3)are combined into a single bundle and the same hollow-fiber membranes(3) are used for blood treatment, filtration of the substituate, anddelivery of the substituate to the blood, that an exterior spacedelimited by the inner wall of the housing (2) and the first and secondsealing compounds (4,5) is formed around the hollow-fiber membranes (3),the exterior space along the longitudinal extent of the housing (2)being separated by the dividing wall (10) into the substituate space(11) and the dialyzate space (12), the dividing wall (10) enclosing eachindividual hollow-fiber membrane (3).
 2. Hemodiafiltration systemaccording to claim 1, characterized in that the dividing wall (10) isarranged substantially transversely to the hollow-fiber membranes (3).3. Hemodiafiltration system according to one or more of claims 1 or 2,characterized in that the means for delivering the substituate and themeans for delivering dialyzate are coupled to each other. 4.Hemodiafiltration system according to claim 3, characterized in that themeans for delivering substituate and the means for delivering dialyzatecomprise a common multiple pump to which a dialyzate supply line (19) incommunication with the dialyzate inlet arrangement (13) and asubstituate supply line (21) in communication with the substituate inletarrangement (15) are connected.
 5. Hemodiafiltration system according toclaim 3, characterized in that the means for delivering dialyzatecomprise a dialyzate delivery device (18) and a dialyzate supply line(19) and the means for delivering substituate comprise a substituatesupply line (21), and that the substituate supply line (21) branches offfrom the dialyzate supply line (19) via a diversion. 6.Hemodiafiltration system according to claim 5, characterized in that asubstituate pump (23) is inserted in the substituate supply line (21)for delivering the substituate.
 7. Hemodiafiltration system according toclaim 5, characterized in that a throttle (22) is inserted in thedialyzate supply line (19) in the area between the diversion and thedialyzate inlet arrangement (13) or into the substituate supply line(21) and the dialyzate supply line (19) in the area between thediversion and the dialyzate inlet arrangement (13), in order to adjustthe ratio of substituate volume stream to dialyzate volume stream. 8.Hemodiafiltration system according to one or more of claims 1 to 7,characterized in that the membrane module (1) in the area of substituatespace (11) has a sterile filter (24) arranged around the bundle ofhollow-fiber membranes (3) and enclosing the bundle. 9.Hemodiafiltration system according to claim 8, characterized in that thesterile filter (24) is a microporous flat membrane. 10.Hemodiafiltration system according to one or more of claims 1 to 9,characterized in that the membrane module (1), viewed in the directionof the longitudinal extent of the housing (2), exhibits a ratioL_(d)/L_(s) of the length L_(d) of the dialyzate space (12) to thelength L_(s) of the substituate space (11) between 3 and
 20. 11.Hemodiafiltration system according to claim 10, characterized in thatthe ratio is between 5 and
 15. 12. Hemodiafiltration system according toone or more of claims 1 to 11, characterized in that the dividing wall(10) of the membrane module (1) is made of a cured sealing compound. 13.Hemodiafiltration system according to claim 12, characterized in thatthe dividing wall (10) and first and second sealing compounds (4,5) aremade of the same material.
 14. Hemodiafiltration system according to oneor more of claims 1 to 13, characterized in that the dividing wall (10)of the membrane module (1) has a thickness between 1 and 15 mm. 15.Hemodiafiltration system according to one or more of claims 1 to 14,characterized in that the housing (2) of the membrane module (1) tightlyencloses, with its inside, the bundle of hollow-fiber membranes (3) inthe area of the dialyzate space (12) and exhibits an expandedcross-section in the area of the sealing compounds (4,5), dividing wall(10), and substituate space (11).
 16. Hemodiafiltration system accordingto one or more of claims 1 to 15, characterized in that the hollow-fibermembranes (3) of the membrane module (1) have an ultrafiltration ratefor water between 20 and 1500 ml/(h·m²·mmHg).
 17. Hemodiafiltrationsystem according to one or more of claims 1 to 16, characterized in thatthe hollow-fiber membranes (3) of the membrane module (1) areimpermeable to endotoxins.
 18. Use of a membrane module (1) having acylinder-shaped housing (2) with a longitudinal extent, in which housing(2) a bundle of hollow-fiber membranes (3) having semipermeable walls,capable of supporting fluid flow through their lumina, and embedded attheir ends in first and second sealing compounds (4,5) joined to theinner wall of the housing (2) in a fluid-tight manner is arranged in thedirection of the longitudinal extent, and in which housing (2) anexterior space delimited by the inner wall of the housing (2) and thefirst and second sealing compounds (4,5) is formed around thehollow-fiber membranes (3), the exterior space along the longitudinalextent of the housing (2) being divided by a continuous dividing wall(10) into a dialyzate space (12) and a substituate space (11) separatedfrom the dialyzate space (12) in a fluid-tight manner, the dividing wallenclosing each individual hollow-fiber membrane (3), to conduct ahemodiafiltration process in which the bundle of hollow-fiber membranesis used, in addition to the actual blood treatment, to filter thesubstituate and deliver the substituate to the blood.
 19. Membranemodule comprising a cylinder-shaped housing (2) with a longitudinalextent, in which housing (2) a bundle of hollow-fiber membranes (3) withsemipermeable walls and capable of supporting fluid flow through theirlumina is oriented in the direction of the longitudinal extent of thehousing (2), the ends of the hollow-fiber membranes (3) being embeddedin a fluid-tight manner in first and second sealing compounds (4,5)joined to the housing inner wall in a fluid-tight manner, such that anexterior space delimited by the first and second sealing compounds (4,5)and the inner wall of the housing (2) is formed around the hollow-fibermembranes, the exterior space along the longitudinal extent of thehousing (2) being divided into a dialyzate space (12) and a substituatespace (11) by a dividing wall (10) that encloses each hollow-fibermembrane (3) and runs substantially transversely to the hollow-fibermembranes (3), the dialyzate space (12) having an inlet arrangement (13)and an outlet arrangement (14) for introducing and withdrawing adialyzate, and the substituate space (11) having at least one inletarrangement (15) for introducing a substituate, characterized in that asterile filter (24) is arranged in the area of the substituate space(11) between the substituate inlet arrangement (15) and the hollow-fibermembranes (3) located in the substituate space (11), the sterile filter(24) dividing the substituate space into an outer substituate-spacesection (25) and an inner substituate-space section (26) that isspatially separated from the outer substituate-space section (25), theouter substituate-space section (25) being in fluid communication withthe substituate inlet arrangement (15) and the hollow-fiber membranes(3) being arranged in the inner substituate-space section (26). 20.Membrane module according to claim 19, characterized in that the sterilefilter (24) is arranged around the bundle of hollow-fiber membranes (3)and encloses the bundle of hollow-fiber membranes (3).
 21. Membranemodule according to one or more of claims 19 or 20, characterized inthat the sterile filter (24) is a microporous flat membrane. 22.Membrane module according to one or more of claims 19 to 21,characterized in that the sterile filter (24) is impermeable toendotoxins.